Cocrystals of nicotinamide riboside salts, crystalline forms, methods of preparation, and applications thereof

Abstract

The present disclosure relates to cocrystals of nicotinamide riboside salts (NR), which can be used in preparing pharmaceutical or nutraceutical compositions for longevity or for the treatment or prevention of cardiovascular diseases, central nervous system diseases, aging, or other conditions. Specifically, the present disclosure relates to the cocrystal of a nicotinamide riboside salt, including but not limited to, the resveratrol cocrystal of nicotinamide riboside chloride, its polymorphic crystalline forms, methods of preparation, and applications thereof.wherein X−is a negatively charged anion, the Coformer (abbreviation of cocrystal former) is a neutral compound or a neutral form of an acid or base, m and n are integers larger than 1.

What is claimed is: 
     
         1 . A cocrystal of a nicotinamide riboside salt has one of the following structures: 
       
         
           
           
               
               
           
         
         wherein X − is a negatively charged anion including but not limited to chloride, bromide, sulfate, phosphate, methyl sulfonate, acetate, malate, tartrate, citrate, fumarate, lactate, maleate, mandelate, malonate, succinate, ascorbate, gluconate, benzoate, besylate, tosylate, hippurate, camsylate, napasylate, napadisylate, stearate, undecylenate, and other acidic counterions; wherein the Coformer (cocrystal former) is a neutral compound or a neutral form of an acid or base, which is selected from any drug excipients included in the GRAS (Generally Recognized as Safe) list published by the FDA; wherein m and n are integers larger than 1; wherein the cocrystal is of anhydrous form, hydrate, solvate, or a mixture thereof; wherein the cocrystal is of a single crystalline form, or a mixture of multiple crystalline forms. 
       
     
     
         2 . The cocrystal of nicotinamide riboside salt according to  claim 1 , wherein X − is the chloride anion, the Coformer is resveratrol; wherein the cocrystal is of anhydrous form, hydrate, solvate, or a mixture thereof, wherein the cocrystal has one of the following structures: 
       
         
           
           
               
               
           
         
         wherein m and n are integers larger than 1. 
       
     
     
         3 . The resveratrol cocrystal of the nicotinamide riboside chloride according to  claim 2 , wherein m=2, n=1; wherein the cocrystal is of a single crystalline form, or a mixture of multiple crystalline forms; wherein the cocrystal has the following chemical structure. 
       
         
           
           
               
               
           
         
       
     
     
         4 . The resveratrol cocrystal of nicotinamide riboside chloride according to  claim 3 , wherein the cocrystal is an anhydrous form, designated as Form A, and is characterized by a PXRD pattern comprising one or more peaks expressed as 2θ±0.2° of about 5.6°, about 11.0°, about 11.3°, about 12.3°, about 13.7°, about 14.0°, about 15.9°, about 19.8°, about 26.0°, and about 26.4;, wherein the PXRD pattern of Form A is shown in  FIG.  2   . 
     
     
         5 . The resveratrol cocrystal of nicotinamide riboside chloride according to  claim 3 , wherein the cocrystal is a solvated form, designated as Form B, and is characterized by a PXRD pattern comprising one or more peaks expressed as 2θ±0.2° of about 5.5°, about 8.2°, about 11.0°, about 12.1°, about 12.9°, about 13.5°, about 15.3°, about 19.6°, about 22.0°, and about 27.0°; wherein the PXRD pattern of Form B is shown in  FIG.  6   . 
     
     
         6 . A method of preparing the resveratrol cocrystal of nicotinamide riboside chloride according to  claim 3  by using recrystallization process. 1) Dissolving the starting materials of nicotinamide riboside chloride and resveratrol in alcohol, water, or their combinations. 2) Concentrating the resulting solution in a vacuum to dryness. 3) Stirring the resulting solid in a dry alcohol solvent. 4) Isolating the resulting crystalline material by filtration, washing, and drying. 
     
     
         7 . A method of preparing the resveratrol cocrystal of nicotinamide riboside chloride according to  claim 3  by using adding anti-solvent process. 1) Dissolving the starting materials of nicotinamide riboside chloride and resveratrol in alcohol, water, or their combinations. 2) Adding anti-solvent of an alcohol into the solution and stirring to produce a homogenous slurry. 3) Isolating the resulting crystalline material by filtration, washing, and drying. 
     
     
         8 . A method of preparing the resveratrol cocrystal of nicotinamide riboside chloride according to  claim 3  by using slurry process. 1) Suspending the starting materials of nicotinamide riboside chloride and resveratrol in a minimum amount of alcohol/water co-solvent. 2) Stirring the suspension until the starting physical mixture fully converted cocrystal to yield a wet-cake. 3) Adding anti-solvent of an alcohol into the resulting wet-cake and stirring to produce a homogenous slurry. 4) Isolating the resulting crystalline material by filtration, washing, and drying. 
     
     
         9 . A composition comprising a cocrystal of a nicotinamide riboside salt according to  claim 1  and a pharmaceutically or nutraceutically acceptable carrier. 
     
     
         10 . The composition according to  claim 9 , wherein the carrier is a diluent, adjuvant, excipient, vehicle, or mixture thereof. 
     
     
         11 . The composition according to  claim 9 , wherein the composition is formulated into tablets, gelcaps, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels, hydrogels, oral gels, pastes, eye drops, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. 
     
     
         12 . The composition according to  claim 9 , wherein the composition is an immediate release composition or extended-release composition. 
     
     
         13 . A method of therapeutic or prophylactic treatment of a subject against central nervous system diseases, cardiovascular diseases, infection diseases, aging, or conditions comprising administration of an amount of a cocrystal of a nicotinamide riboside salt according to  claim 1  to a subject in need of central nervous system diseases, cardiovascular diseases, infection diseases, or conditions care. 
     
     
         14 . A method of therapeutic or prophylactic prevention of a subject against aging, poor mental conditions, poor cardiovascular conditions, or conditions comprising administration of an amount of a cocrystal of a nicotinamide riboside salt according to  claim 1  to a subject in need of anti-aging, longevity, and improvement of mental conditions, cardiovascular conditions, or other conditions.